Human Gut Microbes Transform the Chloroacetamide Herbicide Metazachlor to Metabolites with Altered Toxicological Characteristics

Le résumé fourni par la source

Metazachlor is a globally relevant chloroacetamide herbicide that undergoes microbial biotransformation in the environment, but its transformation by human gut microbiota has not been described. Here, we characterized metazachlor metabolism by human gut microbiota and assessed potential toxicological risks presented by its metabolites. Human fecal microbial communities exposed to metazachlor resulted in 5 known and 17 previously unreported metabolites of metazachlor being identified. Key metabolites were synthesized, and the resulting reference standards were used to confirm structures and elucidate the multistep biotransformation pathway. Cytotoxicity of key metabolites was characterized using human gastrointestinal cell lines, and two of the tested metabolites, namely the thiol of metazachlor M2 and the cysteamine disulfide M6, were more cytotoxic to these cells than metazachlor. Additionally, we confirmed that the thiol M2 had high Caco-2 monolayer permeability, similar to metazachlor. According to physiologically based kinetic modeling of blood concentrations, fast excretion of metazachlor and metabolite levels below cytotoxicity thresholds at the acceptable daily intake level of exposure were anticipated. These findings reveal that metazachlor is extensively metabolized by the human gut microbiota to metabolites with potentially altered biological effects, suggesting their consideration in evaluating human health risks due to metazachlor exposure.

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